No drug is known to be capable of curing Human Immunodeficiency Virus (HIV) infections and Acquired Immunodeficiency Syndrome (AIDS). To date, no vaccine capable of preventing infection by HIV appears within reach.
Existing HIV infections can today, in many cases, be controlled by Highly Active Antiretroviral Therapy (HAART) which involves a combination of three or more retroviral drugs. However, the occurrence of single, double or triple-drug class resistant HIV strains is constantly rising under the selective pressure from the reverse transcriptase and protease inhibitors (RTIs and PIs) currently employed in HAART.
There is therefore an urgent need for new types of anti-HIV drugs. Preferably, such new drugs would target aspects of the virus that are less vulnerable to the development of resistance than reverse transcription and viral maturation processes targeted by the above-mentioned RTIs and PIs. In the absence of an HIV vaccine, there is furthermore a need for agents that are capable of preventing transmission of HIV during sexual contact.
This need could potentially be fulfilled by agents that inhibit the entry of HIV into target cells, i.e., agents from the class of “entry inhibitors” (EI). Such agents could, for example, be locally and topically applied to the human genitals in order to prevent infection of cells by HIV during sexual contact. Agents that can prevent the transmission of HIV during sexual contact are often (though inappropriately) referred to as “microbicides”.
Entry of HIV into human target cells depends upon the attachment of the HIV virion to the human cell surface protein CD4 and a so-called coreceptor. Major coreceptors used by HIV include the seven transmembrane G-protein coupled receptors CXCR4 and CCR5. Natural chemokine ligands of CCR5, in particular RANTES (CCR5), were found to inhibit entry of R5-tropic HIV strains (strains of HIV that use CCR5 as a coreceptor) into human cells [1]. RANTES is a proinflammatory cytokine that is known to promote cell accumulation and activation in chronic inflammatory diseases.
Certain derivatives of RANTES with modifications at the N terminus displayed enhanced anti-HIV activity, e.g., AOP-RANTES, the aminooxypentane oxime of [glyoxylyl]1RANTES (2-68) [2] wherein “(2-68)” denotes residues 2 to 68 of the naturally occurring RANTES peptide. Further chemically modified RANTES derivatives with anti-HIV activity include NNY-RANTES (n-nonanoyl-RANTES (2-68) [3,4]) and PSC-RANTES [5].
However, the chemically modified RANTES derivatives mentioned above not only inhibit HIV entry into cells, but are also relatively strong agonists of CCR5: AOP-, NNY- and PSC-RANTES elicit a pro-inflammatory signalling cascade involving cytosolic calcium influx. The use of agents with such signalling activity as anti-HIV drugs could lead to unwanted side effects involving, e.g., inflammation. Induction of inflammation is a highly undesirable side effect for prophylactic anti-HIV agents, as it has been recognised that the risk of infection by HIV may in fact be increased in inflamed tissue.
Agents such as RANTES derivatives may also induce signalling in target cells due to lack of selectivity or specificity of the agent for CCR5, i.e. in that the agent binds also to the receptor proteins CCR1 and CCR3.
A disadvantage of chemically modified polypeptides is that they cannot be produced by straightforward biotechnological means (expression and fermentation). Fully-coded anti-HIV RANTES derivatives, i.e. derivatives consisting only of naturally encoded amino acids have also been reported [6,7]. However, the anti-HIV potency of all initially reported fully-coded RANTES derivatives was lower than that of the chemically modified variant PSC-RANTES [5].